Cholestyramine, or colestyramine, is an antihyperlipoproteinemic ion exchange resin. It is a very hydrophilic polymer, whose typified structure of main polymeric groups is: ##STR1##
Cholestyramine and similar ion exchange resins, such as colestipol, lower cholesterol by attracting and agglomerating bile acids in the intestinal tract. Once agglomerated, the acids are excreted in feces, and serum LDL levels are lowered. Thus, cholesterol-lowering ion exchange resins are given orally such as in the form of a suspension, confection or a tablet. However, tablets must disintegrate readily so that the resin can act in the intestines.
Although cholestyramine is not water soluble, it rapidly absorbs available moisture, including atmospheric moisture, and swells or softens. This tendency to absorb moisture has led to problems in preparing and administering tablets of cholestyramine. The uncoated tablets are unpalatable and difficult to swallow. The tablets tend to disintegrate in the mouth while swallowing, adding to the unpleasant taste and causing a dry mouth and/or throat that inhibits swallowing. Also, it is well known that resins such as cholestyramine have an inherent unpleasant taste and odor. For these reasons, it is advantageous that the cholestyramine tablets have an adequate coating in order to allow swallowing, without objectionable taste and tablet disintegration in the mouth and/or throat.
The process for aqueous film coating of cholestyramine tablets is problematic because the resin readily absorbs moisture during the coating process. This causes tablets to swell and to undergo disintegration and surface erosion. Due to this moisture problem, the disclosure of U.S. Pat. No. 5,372,823 considered aqueous film coating of cholestyramine tablets to be impractical.
Attempts to film coat using a non-aqueous film-coating process were also found to be unsuccessful for cholestyramine, as the resin absorbed and retained unacceptably high levels of non-aqueous solvents as described in U.S. Pat. No. 5,372,823.
Several methods for avoiding these coating problems have been advanced.
Bequette, et at. in U.S. Pat. No. 5,372,823 and 5,455,047 describe the direct compression of cholestyramine powder into agglomerated cores which are then coated with a mixture of stearic acid and polyethylene glycol.
U.S. Pat. No. 4,843,098 to Shaw, et al. deals with cholestyramine resin formulations in which the "preswelled" resin is coated with hydrocolloid.
The hydrocolloid may be hydroxypropyl methycellulose. However, these preswelled resin formulations add to the weight and size of the tablets. Since 4-8 g doses of cholestyramine, given twice daily, are required, these large-sized, higher-weight tablets are undesirable as the dose must be taken as either hard-to-swallow larger tablets or a large number of smaller tablets. This adds to the problems of dose management and compliance.
Amer, et al. in U.S. Pat. No. 4,895,723 dealt with the production of a solid cholestyramine product. During processing the resin is blended with a syrup containing hydroxypropylmethylcellulose. That syrup forms a paste or dough from which a power can be made. Again, due to the considerably increased bulk, the cholestyramine formulations of Amer are best given by incorporation into a confection or beverage type of product formulation.
U.S. Pat. No. 5,447,726 of Nomura disclosed the tableting of 2-methylimidazole-dichloro-hydrin copolymer resin (MCI-196). MCI-196 is a cholesterol-lowering ion exchange resin whose general structural formula is: ##STR2##
Inner tablets for coating are prepared by blending MCI-196 with hydroxypropylmethylcellulose in the presence of 14-20% by weight of water and up to 2% hydrated silica to make a granulate; mixing with lubricant; and then compressing. The disclosure emphasizes that at least 14% water must be added to MCI-196 in order to insure that the aqueous cellulosic coating will adhere to the resin. Nomura's tablets contain from 2-5% by weight of coating material comprised of hydroxypropylmethylcellulose, titanium oxide, talc and polyethylene glycol.
In U.S. Pat. No. 5,091,175, Imondi, et al. describe the enclosing of ion exchange resins with a non-degradable cellulosic coating to provide a semipermeable coat. The nature of the coating permits bile acids to react with the resin but prevents larger molecules from contacting and binding to the resin.
Tablets produced by these procedures have certain drawbacks. Some of these tablets are difficult to swallow. Waxy coatings on cholestyramine tablets become brittle and tend to chip. Once atmospheric moisture penetrates the chipped coating, cracks form when the hydrophilic resin swells. Subsequently, the tablet coating layer dissolves or disintegrates in a person's mouth, causing the hydrophilic ion exchange resin to come in contact with moist tissues of the oral cavity. In these instances, "gagging," "cotton mouth" or "dry mouth" resulted, leading to compliance problems. Further, waxy-coated tablets in general provide a weak coat that is non-expandable, inherently porous and whose film coat integrity is very temperature dependent. Thus, waxy coatings are generally not acceptable.
In addition, the large daily dose required for cholestyramine (from 4-8 g twice a day) gave rise to tablets containing 1 g of resin in order to make fewer units to swallow. The size of these tablets made them difficult to swallow. While 1 g tablets were preferred, the combination of their size and the failure to effectively prevent disintegration in the mouth/throat while swallowing gave rise to reports of patient choking.
It became clear that a reduction in tablet size and development of a new method of tablet coating of cholestyramine or other hydrophilic ion exchange resins was needed. Ideally, this method would overcome problems affecting compliance and contribute to easy-to-swallow tablets. The tablets should be smaller in size and of a shape making them easy to swallow. It would also be required that such tablets do not disintegrate in the mouth or throat during swallowing but disintegrate readily in the stomach after being swallowed.
It is the general object of this invention to make an easy-to-swallow tablet of an orally administrable cholesterol-lowering resin such as cholestyramine. In this regard, specific objectives are:
smaller sized tablets, PA1 containing mainly resin to minimize the number of tablets that must be taken, PA1 easy-to-swallow tablet shape, PA1 tablet intact during swallowing, PA1 tablet readily disintegrates in the stomach, and PA1 tablet stable under the temperature and humidity conditions commonly encountered in pharmaceutical production, shipping and storage.
It is a further objective to develop a manufacturing process for preparation of the improved cholestyramine tablets that incorporates not only efficiencies of materials and processing steps, but also minimizes tablets with coating defects. Such a process would provide tablets maximizing the resin content and minimizing tablet excipients.
There is nothing in the prior art that discloses or suggests the novel combination of tablet formulation modifications that produce the improved, easy-to-swallow tablets of orally administrable cholesterol-lowering resin of this invention.